There is a need for improved antiparasitic agents for use with animals, and in particular there is a need for improved long-acting (i.e., 6-months) insecticides and acaricides. Furthermore there is a need for improved topical and oral products with convenient administration and which contain one or more of such antiparasitic agents which can be used to effectively treat ectoparasites, such as insects (e.g., fleas, lice, and flies) acarids (e.g., mites and ticks), and copepods (e.g., sea lice). The compounds of the present invention can also be used as an endoparasiticide to effectively treat helminthes, for example, cestodes (tapeworms), nematodes (roundworms), and trematodes (flukes). Such products would be particularly useful for the treatment of animals (e.g., cat, dog, horse, cattle, swine, sheep, goats, birds, and fish).
The compounds currently available for insecticidal, acaricidal, and helminth treatment of companion animals and livestock do not always demonstrate good activity, good speed of action, or a long duration of action. Most treatments contain hazardous chemicals that can have serious consequences, including lethality from accidental ingestion. Persons applying these agents are generally advised to limit their exposure. Pet collars and tags have been utilized to overcome some problems, but these are susceptible to chewing, ingestion, and subsequent toxicological affects to the animal. Thus, current treatments achieve varying degrees of success which depend partly on toxicity, method of administration, and efficacy. Currently, some agents are actually becoming ineffective due to parasitic resistance.
Diphenyl-3,4-dihydro-2H-pyrrole derivatives and 1,3-diphenylpyrrolidine derivatives have been disclosed in the art as having insecticidal and acaricidal activity. For example, JP2012031148 and WO2012/035011. Further, WO2007/075459 discloses phenyl isoxazolines substituted with 5- to 6-membered heterocycles. WO2011/101229 discloses certain dihydrofuran derivatives as antiparasitic agents. Certain isoxazoline-azetidine derivatives were disclosed in WO2012/017359. However, the citations do not describe the non-isoxazole azetidine derivatives of the instant invention, nor does the prior art indicate that such compounds would be useful against a spectrum of parasitic species, regardless of morphological lifecycle stages, in animals.
Despite the availability of effective, broad spectrum antiparasitic agents, there remains a need for a safer, convenient, efficacious, and environmentally friendly product that will overcome the ever-present threat of resistance development.
The present invention overcomes one or more of the various disadvantages of, or improves upon, the properties of existing compounds. In particular the present invention develops new azetidine derivatives which demonstrate such properties.